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Additive manufacturing can easily produce products with complex shapes and multiple components. This has advantages in terms of lead time and costs over traditional machining. In this regard, the recent trend of the launch vehicle targets to low-cost launch vehicles, and additive manufacturing is being applied to the production of the low-cost launch vehicles [1]. The fuel (LCH4) in the methane expander cycle engine cools the thrust chamber and vaporizes, so it is supplied as a gas to the injector head. Methane is also generally supplied to the bottom manifold to cool the faceplates of the injector heads (manifold and injectors). The injector mixes and atomizes propellants in the combustion chamber. The atomization/mixing performance affects the combustion performance of the rocket engine, and depends on injector design parameters such as recess length and taper angle. The propellant combination is a liquid oxidizer/gas fuel in the injector, in which case a swirl coaxial injector with good performance and stability is applied [2]. In this study, additive manufacturing was applied to manufacture a new manifold cooled by an oxidizer and the internal structure of an injector that is difficult to implement with machining. Cryogenic oxidizer (LOx) that has cooled the faceplate of the injector head passes through a tangential hole and is supplied into the central oxidizer injector with a swirl motion. The fuel (GCH4) supplied from the upper manifold is swirled by the vane and injected into the combustion chamber. The initial injector head was manufactured to have a recess length (LR) of 0 mm and a full taper angle of 7.5 by the SLM (Selective laser melting) method using UNS S31603 single material. To confirm the effect of the recess length on the combustion characteristics, the injector of the head was electric discharge machined to have LR = 2 mm and LR = 4 mm after hot firing tests. Hot-firing tests were performed at the 1 kN-class methane engine combustion test facility [3]. Each injector was tested several times in various mixture ratio ranges. The combustion efficiency of the injector with LR = 2 mm was not improved compared to the result of LR = 0 mm. On the other hand, the combustion efficiency of the injector with LR = 4 mm was improved due to the advanced atomization and mixing [4]. The average heat flux of LR = 4 mm was high due to the improvement of combustion pressure and combustion efficiency. All hot-firing tests were performed without combustion instability so that pressure fluctuations in the injector manifold was less than 0.41% of the chamber pressure. Finally, no damage was found on the faceplate and injector after a total of 300 seconds of cumulative hot-firing tests.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population. ispartof: NEUROLOGY vol:97 issue:11 pages:528-536 ispartof: location:United States status: published

This article presents a fatigue model that can robustly capture the effect of high surface roughness on the fatigue crack initiation of additively manufactured Ti6Al4V (AM Ti64) alloys in the moderate cycle fatigue regime based on nonlinear finite element (FE) analyses and the theory of critical distances. We propose two methods to use surface measurements of AM components to create FE models, viz., surface topography of the component is explicitly represented in the FE models or a simplified geometrical model, which has only a single sinusoidal-shaped notch, is proposed to replace the surface topography in the FE models. The geometrical parameters of the simplified model are derived based on the MOTIF method (ISO 12085) and its parameters are determined by using the leave-one-out cross-validation method. In the moderate cycle fatigue regime, the stress applied to components is below the yield stress, but the high surface roughness acts as a stress raiser and causes local plasticity at surface valleys. Thus, a nonlinear hardening elasto-plasticity model is employed in the FE models to capture the cyclic mechanical behavior of AM Ti64 alloys. Afterward, the fatigue analyses are performed by employing our in-house C++ software within which fatigue indicator parameters (FIPs) are computed by post-processing the finite element results. In the present work, the Smith-Watson-Topper (SWT) parameter is used as an FIP and is computed at every element in the FE mesh, i.e., the local FIP. Subsequently, to account for the stress gradient effect in the proposed fatigue model, the SWT parameter is averaged over a so-called critical area to compute a nonlocal FIP. The physical fidelity of the proposed fatigue model is shown by a good agreement between the predicted fatigue life cycles based on the nonlocal FIP and the corresponding experimental data. Moreover, the predicted fatigue cycles obtained from the simplified geometrical model also yield good accordance to the experimental data, thus we can model the effect of the surface roughness on the fatigue properties of AM Ti64 in an efficient way.

The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics., Sensitive and label-free imaging methods to visualize nerve degeneration are currently lacking. Here authors show that stimulated Raman scattering (SRS) microscopy can be used to monitor peripheral nerve degeneration in mouse models of amyotrophic lateral sclerosis (ALS) and in postmortem tissue from ALS patients.

Direct laser melting(DLM) is an additive manufacturing process that can produce parts by solidification of molten metallic powder layer by layer. The properties of the fabricated parts strongly depend on characteristics of the metallic powder. Atomized powders having spherical morphology have commonly been used for DLM. Mechanical ball-milling is a powder processing technique that can provide non-spherical solid powders without melting. The aim of the current study was to investigate the effect of powder morphologies on the deposition quality in DLM. To characterize the morphological effect, the performances of spherical and non-spherical powders were compared using both single- and multi-track DLM experiments. DLM experiments were performed with various laser process parameters such as laser power and scan rate, and the deposition quality was evaluated. The surface roughness, cross-section bead shape and process defects such as balling or non-filled area were compared and discussed in this study.

Operating under elevated temperature and high stress for long terms, the regularly cubic γ ' precipitates of the Ni-based superalloy degrades to plate-like morphology perpendicular to the external stress. This process is called rafting and plays a deteriorated role on the mechanical properties of the alloy. In this study, the quantitative effect of rafting on the low cycle fatigue behaviour of a directionally solidified Ni-based superalloy was investigated. Fatigue tests were conducted at 850 °C with a 1.1% total strain range with six different rafting states. The fatigue life decreased considerably over 90% as the rafting state aggravated. The rafting process increased the width of the matrix channel, which weakened the plastic deformation resistance and the mean stress relaxation of the superalloy. To build a quantitative relationship between the life reduction and rafting state, a life prediction model was proposed based on the strengthening mechanism of Ni-based superalloys by assuming that the rafted alloy suffered a higher loading level compared with the virgin state. Moreover, the scanning electron microscopy was employed to observe fatigue fracture surfaces and the rafted microstructures. The micro-parameters such as the width of the γ ' precipitates and the matrix channel were obtained through a cross-correlated image processing method.

During roll forming a sheet metal is continuously and progressively formed into a product of the required cross-section and longitudinal shape. An example product is a circular tube with a required diameter, wall-thickness and straightness. Roll forming occurs by passing the sheet through a series of forming rolls that are arranged in tandem. Each pair of forming rolls in the roll forming line plays a particular role in obtaining the required cross-section and longitudinal shape in the product. In recent years, that process is often applied to car body parts by automotive industries. In the current study, an optimal model design and proper roll-pass sequences as well as the number of forming rolls and bending angles were used to produce a sill side. The effects of the process parameters on the final shape formed by roll forming defects were evaluated.

Mutations in the nuclear RNA-binding protein FUS can cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Study of ALS patient fibroblasts reveals FUS protein aggregated in the nucleus and its regulation of RNA polymerase II disrupted. Thus mutant FUS need not be aggregated in the cytoplasm to have deleterious consequences., Mutations in the RNA-binding protein FUS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigate whether mutant FUS protein in ALS patient–derived fibroblasts affects normal FUS functions in the nucleus. We investigated fibroblasts from two ALS patients possessing different FUS mutations and a normal control. Fibroblasts from these patients have their nuclear FUS protein trapped in SDS-resistant aggregates. Genome-wide analysis reveals an inappropriate accumulation of Ser-2 phosphorylation on RNA polymerase II (RNA Pol II) near the transcription start sites of 625 genes for ALS patient cells and after small interfering RNA (siRNA) knockdown of FUS in normal fibroblasts. Furthermore, both the presence of mutant FUS protein and siRNA knockdown of wild-type FUS correlate with altered distribution of RNA Pol II within fibroblast nuclei. A loss of FUS function in orchestrating Ser-2 phosphorylation of the CTD of RNA Pol II is detectable in ALS patient–derived fibroblasts expressing mutant FUS protein, even when the FUS protein remains largely nuclear. A likely explanation for this loss of function is the aggregation of FUS protein in nuclei. Thus our results suggest a specific mechanism by which mutant FUS can have biological consequences other than by the formation of cytoplasmic aggregates.

Functionally graded properties are characterized by the gradual variation in composition and structure through the volume of the material, resulting in corresponding gradation in properties of the material. Direct laser melting (DLM) is a prototyping process whereby a 3-D part is built layer-wise by melting metal powder with laser scanning. Studies have been performed on the functionally graded properties induced by direct laser melting of compositionally selected metallic powders. For the current study, quadrangle structures were fabricated by DLM using Fe-Ni-Cr powders having variable compositions. Hardness and EDX analysis were conducted on cross-sections of the fabricated structure to characterize the properties. From the analysis, it is shown that functionally graded properties can be successfully obtained by DLM of selected metallic powders with varying compositions.

SummaryAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.

SummaryThe RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

The use of roll-formed products increases every year due to its advantages, such as high production rates, reduced tooling cost and improved quality. However, till now, it is limited to part profiles with constant cross section. In recent years, the flexible roll forming process, which allows variable cross sections of profiles by adaptive roll stands, was developed. In this study, an attempt to optimize profile design for the flexible roll forming process was performed. An equation that predicts the longitudinal strain for part geometries with variable cross-sections was proposed. The relationship between geometrical parameters and the longitudinal strain was analyzed and investigations on the optimal profile design were performed. Experiments were conducted with a lab-scale roll forming machine to validate the proposed equation. The results show that the profile design method proposed in this study is feasible and parts with variable cross sections can be successfully fabricated with the flexible roll forming process.

Direct Laser Melting is a prototyping process whereby a 3-D part is built layer wise by melting the metal powder with laser scanning. This process is strongly influenced by the shielding gas and the laser operating parameters such as laser power, scan rate, layering thickness, and rescanning. The shielding gas is especially important in affecting the microstructure and mechanical properties. In the current study, fabrication experiments were conducted in order to analyze the effect of shielding gas on the forming characteristics of direct laser melting. Cylindrical parts were produced from a Fe-Ni-Cr powder with a 200W fiber laser. Surface quality, porosity and hardness as a function of the layering thickness and shield gas were evaluated. By decreasing the layering thickness, the surface quality improved and porosity decreased. The selection of which shield gas, Ar or , to obtain better surface quality, lower porosity, and higher hardness was examined. The formability and mechanical properties with a atmosphere are better than those parts formed under an Ar atmosphere.

Tube hydroforming is a technology that utilizes hydraulic pressure to form a tube into desired shapes inside die cavities. Due to its advantages, such as weight reduction, increased strength, improved quality, and reduced tooling cost, single-layered tube hydroforming is widely used in industry. However in some special applications, it is necessary to produce multi-layered tubular components which have corrosion resistance, thermal resistance, conductivity, and abrasion resistance. In this study, a hollow forming process to fabricate a part from multi-layered tubes for structural purposes is proposed. To accomplish a successful hydroforming process, an analytical model that predicts optimal load path for various parameters such as tube material properties, thickness of tubes, diameter of holes and the number of holes was developed. Tubular hydroforming experiments to fabricate a hollow part were performed and the optimal loading path developed by the analytical model was successfully verified. The results show that the proposed hydroforming process can effectively produce hollow parts with multi-layered tube without defects such as wrinkling or fracture.

Among the disciplines of medicine, the study of neurological disorders is particularly challenging. The fundamental inaccessibility of the human neural types affected by disease prevents their isolation for in vitro studies of degenerative mechanisms or for drug screening efforts. However, the ability to reprogram readily accessible tissue from patients into pluripotent stem (iPS) cells may now provide a general solution to this shortage of human neurons. Gradually improving methods for directing the differentiation of patient-specific stem cells has enabled the production of several neural cell types affected by disease. Furthermore, initial studies with stem cell lines derived from individuals with pediatric, monogenic disorders have validated the stem cell approach to disease modeling, allowing relevant neural phenotypes to be observed and studied. Whether iPS cell-derived neurons will always faithfully recapitulate the same degenerative processes observed in patients and serve as platforms for drug discovery relevant to common late-onset diseases remains to be determined.

As formability of magnesium alloys is highly dependent upon temperature and strain rate at elevated temperatures, a new approach of incorporating strain rate and temperature effects into a failure criterion is necessary. In the present study, two failure criteria were proposed to predict the fracture behavior of magnesium alloy sheets deforming at elevated temperatures. The two failure criteria were developed based on the effective strain or damage parameters and both could be formulated as a function of Zener–Holloman parameter. The experimental data obtained from the series of tensile tests conducted in wide range of temperature and strain rate were used to find the correlation between the damage value at fracture (or fracture strain) and Zener–Holloman parameter. Comparison between the experimental results and the prediction by FEM incorporated with the failure criteria indicated that the proposed criteria were useful in predicting the fracture behavior of magnesium alloy sheets deforming during deep drawing process.

This study evaluates the factors affecting pretreatment conditions for hybrid UF membrane processes for reuse of secondary effluent from the sewage treatment plant. The experimental results obtained from the ultrafiltration (UF) membrane process showed that the particles of the size range between 0.2 and 1.2 μm caused a significant impact on membrane fouling in all cases even with or without the coagulation process. As pretreatment of UF membrane process, the coagulation significantly improved the permeate flux. Optimal flux improvement was seen at an alum dose of 50 mg/L. In addition, it was found that the permeate flux was least declined under the coagulation condition of charge neutralization (pH 5.0). Also, the powdered activated carbon (PAC) adsorption enhanced the permeate flux. Application of the direct filtration as a pretreatment of UF membrane process was also very effective in reducing the UF membrane fouling.

In the case of MEMS and NEMS, the mechanical properties of their materials are closely related to their performance and reliability. The measurement of the mechanical properties of thin film for MEMS/NEMS is difficult because of the small sizes, forces, and displacements involved as well as the need for special techniques to prepare and handle the specimens. In general, micromechanical tests involve three main issues; specimen preparation, force application and measurement, and displacement or strain measurement. The microtensile testing system was developed. The grip ends of the specimen are glued to the grips attached to a piezoelectrically actuated loading system. Strain is measured directly on the specimen with laser interferometry named ISDG. Au is one of most widely used materials in microelectromechanical systems. Au film in the pattern is deposited on Si substrate by sputtering process, of which thickness is 1 μm. For strain measurement the markers on the specimen was made by focused ion beam (FIB). Using the microtensile test, stress–strain curve, elastic modulus and ultimate tensile strength of Au thin film was obtained. The results were compared with those of nanoindentation test.

A better efficiency of sensing tera-hertz signals (T-rays) depends on a better crystalline structure which is obtained by replacing a small amount of Cd on Zn sites of ZnTe crystals. Zn1-xCdxTe (ZCT) crystals were fabricated with an advanced vertical Bridgeman method and the structural properties of the ZCT crystals were studied with high resolution x-ray diffraction (HRXRD) and x-ray absorption fine structure (XAFS) measurements. The Rietveld refinement to the HRXRD data showed that the ZCT crystals at x ~ 0.05 were slightly less disordered than the ZnTe crystals. These results were confirmed by the XAFS data analysis. The better structural orderings can be directly related to the sensing and emitting efficiencies of T-ray by the ZCT crystals.

A 2.2-inch QCIF+(176RGB220) TFT-LCD with integrated row driver was developed using a standard amorphous silicon TFT technology. At low temperature, the integrated row driver operation is dramatically effected by the electron drift mobility reduction(■50 %) and the threshold voltage shift (■1V) of the a-Si TFT. We studied the dependency of circuit design and found that higher on-current circuit is important to guarantee good operation in wide temperature range.

Using a sample of 58×10 6 J / ψ events collected with the BESII detector, radiative decays J / ψ → γγV , where V = ρ or φ , are studied. A resonance around 1420 MeV/ c 2 ( X (1424)) is observed in the γρ mass spectrum. Its mass and width are measured to be 1424±10(stat)±11(sys) MeV/ c 2 and 101.0±8.8±8.8 MeV/ c 2 , respectively, and its branching ratio B ( J / ψ → γX (1424)→ γγρ ) is determined to be (1.07±0.17±0.11)×10 −4 . A search for X (1424)→ γφ yields a 95% C.L. upper limit B ( J / ψ → γX (1424)→ γγφ ) −4 .

Multiple classes of precursor cells have been isolated and characterized from the developing spinal cord including multipotent neuroepithelial (NEP) stem cells and lineage-restricted precursors for neurons (NRPs) and glia (GRPs). We have compared the survival, differentiation and integration of multipotent NEP cells with lineage-restricted NRPs and GRPs using cells isolated from transgenic rats that express the human placental alkaline phosphatase gene. Our results demonstrate that grafted NEP cells survive poorly, with no cells observed 3 days after transplant in the adult hippocampus, striatum and spinal cord, indicating that most CNS regions are not compatible with transplants of multipotent cells derived from fetal CNS. By contrast, at 3 weeks and 5 weeks post-engraftment, lineage-restricted precursors showed selective migration along white-matter tracts and robust survival in all three CNS regions. The grafted precursors expressed the mature neuronal markers NeuN and MAP2, the astrocytic marker GFAP, the oligodendrocytic markers RIP, NG2 and Sox-10, and the synaptic marker synaptophysin. Similar behavior was observed when these precursors were transplanted into the injured spinal cord. Predifferentiated, multipotent NEP cells also survive and integrate, which indicates that lineage-restricted CNS precursors are well suited for transplantation into the adult CNS and provide a promising cellular replacement candidate.

Cerebrovascular anomalies such as aneurysms and arteriovenous malformations (AVMs) are rare but important causes of intracerebral hemorrhage (ICH) and are associated with a significantly higher risk of rebleeding; early detection and treatment are crucial.

Using a sample of 5.8X10E7 J/$\psi$ events, the Beijing Spectrometer experiment has searched for the decay J/$\psi \to e\mu$. Four candidates, consistent with the estimated background, are observed, and an upper limit on the branching fraction of J/$\psi \to e\mu$ of 1.1X10E-6 at the 90% C.L. is obtained.

The KLOE experiment has been collecting data since April 1999 at the DAΦNE e+-e− collider at a center of mass energy equal to the o-meson mass. A total amount of 5 × 107 o decays have been analyzed. Results concerning the measurement of the semileptonic branching ratio of the KS, the measurement of the ratio BR(KS → π+π−)BR(KS → π0π0) and the study of the radiative decays of the o involving η, η′, ƒ0(980) and a0(980) are presented.

Multipotent neural stem cells (NSCs) have the potential to differentiate into neuronal and glial cells and are therefore candidates for cell replacement after CNS injury. Their phenotypic fate in vivo is dependent on the engraftment site, suggesting that the environment exerts differential effects on neuronal and glial lineages. In particular, when grafted into the adult spinal cord, NSCs are restricted to the glial lineage, indicating that the host spinal cord environment is not permissive for neuronal differentiation. To identify the stage at which neuronal differentiation is inhibited we examined the survival, differentiation, and integration of neuronal restricted precursor (NRP) cells, derived from the embryonic spinal cord of transgenic alkaline phosphatase rats, after transplantation into the adult spinal cord. We found that grafted NRP cells differentiate into mature neurons, survive for at least 1 month, appear to integrate within the host spinal cord, and extend processes in both the gray and white matter. Conversely, grafted glial restricted precursor cells did not differentiate into neurons. We did not observe glial differentiation from the grafted NRP cells, indicating that they retained their neuronal restricted properties in vivo. We conclude that the adult nonneurogenic CNS environment does not support the transition of multipotential NSCs to the neuronal commitment stage, but does allow the survival, maturation, and integration of NRP cells.

We have measured the branching ratio BR( φ → π 0 π 0 γ ) with the KLOE detector using a sample of ∼5×10 7 φ decays. φ mesons are produced at DA Φ NE, the Frascati φ -factory. We find BR( φ → π 0 π 0 γ )=(1.09±0.03 stat ±0.05 syst )×10 −4 . We fit the two-pion mass spectrum to models to disentangle contributions from various sources.

We present a measurement of the branching ratio BR(KS --> pi e nu) performed using the KLOE detector. KS mesons are produced in the reaction e+ e- --> phi --> KS KL at the DAFNE collider. In a sample of about 5 million KS-tagged events we find 624 +- 30 semileptonic KS decays. Normalizing to the KS --> pi+ pi- count in the same data sample, we obtain BR(KS --> pi e nu) = (6.91 +- 0.37) 10^-4, in agreement with the Standard Model expectation., Comment: 9 pages, 5 Encapsulated Postscript figures. Submitted to Phys. Lett. B